N-substituted pyrrolo-pyridine derivatives



United States Patent 3,497,507 N- SUBSTITUTED PYRROLO-PYRIDINE DERIVATIVES Meier E. Freed, Philadelphia, Pa., assignor to American "ice The above compounds and their salts have central nervous system action, demonstrating stimulant and psychic energiser activity as well as an ability to counteract symptoms related to parkinsonism.

In preparing compounds falling within the designated gf g g gggs gg New York a Formula I, the selected pyrrolo-pyridine is first reacted No Drawing. Filed June 27, 1966, Ser. No. 560,811 Wlth an alkali metal or alkali metal derivative to activate hm CL 07 57 /04 i the pyrrolo nitrogen. For this purpose, one may use an 11,5;(11, 260-4475 5 Cl i alkali metal, such as sodium or potassium, alkali metal hydrides, preferably sodium hydride, alkali metal amides,

such as sodamide or potassium amide, or alkali metal alco- ABSTRACT OF THE DISCLOSURE holates, preferably sodium ethylate. This reaction is nor- N substituted-cyclopolymethylene-pyrrolopyridines are many Famed out usm.g a splvent such tolu' prepared having useful pharmacological activity, particudfmethyl'forlnamlde dlmefhylacetamlde. or dlmethyl lady on the central nervous system sulf oxide. Following the formation of the sodio or potassic p derivative, the latter is then reacted ll'l one of a number of ways.

This invention relates broadly to pyridyl derivatives and one route 18 t react the alkah'acnvated comBmmd Wlth more particularly to N-substituted pyrrolo-pyridines, the an alkyl y hahde for.example methylene acid-addition and quaternary ammonium salts thereof and 20 chlorobronllde or .am1POethy1Ch1on.de to methods for their preparation When using a dihallde, the react1on product which now Compounds of the invention may be illustrated by the contams F halogen. atom 9 the alkyllanfe cham 15 formula: treated with an amine or nitrogen-containing heterocyclic,

thus forming, by this route, a compound of Formula I. When the alkali-activated compound is reacted with an (CH2), alkyl halide or aminosubstituted alkyl halide or similar reactant, compounds of Formula I are directly formed. N N Alternatively, one may react the activated pyrrolopyri- (I) dine compound with a cyano compound having an unsaturated alkyl chain, for example, acrylonitrile or vinylwherein R is intended to represent an alkyl or substituted acetonitrile. The cyanoalkyl-pyrrolopyridine may then be alkyl chain. Thus, R is intended to represent an alkyl, reduced, using for example, lithium aluminum hydride, aryloxyalkyl or arylalkyl radical, or an aminoalkyl, alkylthus converting the cyano group to an amino radical. aminoalkyl, dialkylaminoalkyl or a heterocyclic nitrogen- To make the N-mono or N,N-disubstituted amino comcontaining radical attached to the alkyl chain, such as pound, or its equivalent, the unsubstituted amino is reacted pyrrolidinoalkyl, piperidinoalkyl or morpholinoalkyl. The with the appropriate halide in known manner. ring containing the-designation (CH is intended to rep- To further illustrate the routes leading to the prepararesent a polymethylene ring, with n standing for an integer tion of the compounds of Formula I, the following flowfrom 4 to 11 inclusive. diagram will show the various methods:

q RX (CH2)u y (0112),. a tl i t iii g U \N agent N N I? H R X-AX/\H2=CH.CN II 1 III I fly W" (CH2); (0112) M N N N N A. ((|3H2)2 IIC IV (IIN V R1 \(reduction) W O W i (CH2)u In In (0112)" L. l l (0112) \N N/K) \\.N/\N/\} \NAN Z L i zh In the above illustrative fiow diagram, it will be seen that the compounds of Formula I may be made by different routes as shown, the selected route at times depending on the type of compound desired. The letters R and n have the same meanings as previously given. The letter A is intended to represent a lower alkylene radical. The designation X is intended to stand for a halogen atom, preferably chlorine or bromine. The amino reactant is intended to stand for a primary or secondary alkylamine with R and R representing hydrogen or lower alkyls of 1 to 3 carbon atoms, but these may be connected together with the nitrogen atom to represent a nitrogencontaining heterocyclic radical, for example, pyrrolidine, piperidine or morpholine. The symbol Z is intended to represent a monoor di-lower alkylaminoalkyl chain, while the symbol Z' is similar to Z but in addition may represent a 5- or 6-membered heterocyclic nitrogen-containing radical.

The starting compounds, represented by Formula II, may be prepared in known manner, it not commercially available. One procedure for making the tricyclic compounds is disclosed by Okuda et al., J.A.C.S. 81, p. 740 (1959).

As indicated previously, the compounds are also useful either as non-toxic, pharmaceutically acceptable monoor di-acid-addition salts or as quaternary ammonium compounds. These may be prepared in known manner, utilizing the selected mineral or organic acid or hydrocarbon halide as the case may be. The reaction is generally carried out in an organic solvent, for example ether. Typical acids may be hydrochloric, sulfuric, phosphoric, acetic, fumaric or maleic acids. For preparing the quaternary salts, the base is reacted with the selected halide, for example methyl or benzyl chloride.

The compounds may be administered orally or parenterally, either in a single dose within the range of 1 mg. to 200 mg. per kilogram of body weight per day, or in divided doses, in the form of tablets, capsules or as solutions or suspensions. If desired, the solids may include carriers, excipients or diluents. The liquid form may be either aqueous or oleagenous.

EXAMPLE 1 A solution of 5,6,7,8-tetrahydro-9H-pyrid[2,3-b]indole (4.0 g., 0.0232 mole) in dimethyl formamid (35 ml.) was added to a stirred suspension of sodium hydride (1.15 g., 0.0256 mole of a 53% dispersion in mineral oil). Stirring was continued for 1 hour at room temperature. Freshly distilled fl-diethylaminoethylchloride (3.15 g., 0.0232 mole) was added. Stirring was continued at 40 50 C. for 4 /2 hours, then at room temperature for hours. The mixture was poured into ice water (400 ml.) and treated with acetic acid to pH 6. It was extracted with ether (3 portions, 100 ml. each). The aqueous phase was made strongly basic with excess sodium hydroxide (50% aqueous solution) and extracted with ether (4 portions, 250 ml. each and 1 portion of 100 ml.). The ethereal extracts were combined, washed twice with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the drying agent and the solvent gave the crude base as an oil, 5.9 g. The base was dissolved in ether (400 ml.) and treated with anhydrous hydrogen chloride. The desired product, 9-[2-(diethylamino) ethyl] 5,6,7,8-tetrahydro-9H-pyrido [2,3-b] indole as the hydrochloride salt, was collected by filtration and recrystallized from methanol-acetone to give the product, 4.25 g., melting at 235-237 C.

Analysis for c qHgqclzNg calculated: C, 59.31%; H, 7.91%; Cl, 20.59%; N, 12.21%. Found: C, 59.81%; H, 7.89%; Cl, 20.30%; N, 12.00%.

A second crop was obtained, 0.76 g., melting at 232- 235 C., bringing the total yield to 62.9%.

EXAMPLE 2 1l-[2-(diethylamino)ethyl] 5,6,7,8,9,10 hexahydro- 11H cyclooct[4,5]-pyrrolo[2,3-b]pyridine is prepared from 5,6,7,8,9,10 hexahydro-11H-cyclooct[4,5]pyrrolo [2,3-b] pyridine, sodium hydride and B-diethylaminoethylchloride in dimethyl formamide in the same manner as described in Example 1. The hydrochloride melts at 178- 181 C. I

Analysis for C H Cl N calculated: C, 61.30%; H, 8.39%; Cl, 19.04%; N, 11.29%. Found: C,'61.77%; H, 8.17%; Cl, 18.90%; N, 11.18%.

EXAMPLE 3 I Y 9-[3-(dimethylamino)propyl] 5,6,7,8-tetrahydro-9H- pyrido-[2,3-b]indole is prepared from-5,6,7,8-tetrahydro- 9H-pyrid[2,3-b]indole, sodium hydride and 'y-dimethylaminopropyl chloride in dimethyl formamide in the same manner as described in Example 1. The hydrochloride melts at 229232 C.

Analysis for C H Cl N calculated: C, 58.16%; H, 7.63%; CI, 21.47%; N, 12.72%. Found: C, 58.02%; H, 7.81%; Cl, 21.00%; N, 12.9%.

EXAMPLE 4 EXAMPE 5 5,6,7,8,9,l0-hexahydro-11-(2 morpholinoethyl)-1ll-lcyclooct[4,5]pyrrolo[2,3 b]pyridine is prepared from 5,6,7,8,9,10-hexahydro-1lH-cyclooct[4,5]pyrrolo[2,3 b] pyridine, sodium hydride and fi-morpholinoethyl chloride in dimethyl formamide in the same manner as described in Example 1. The hydrochloride melts at 2-63- 266 C.

Analysis for C H Cl N O calculated: C, 59.08%; H,

p 7.57%; Cl, 18.35%; N, 10.86%. Found: C, 59.12%; H,

7.77%; Cl, 18.00%; N, 10.57%.

EXAMPLE 6 9-[2(morpholino)ethyl] 5,6,7,8-tetrahydro-9H-pyrido [2,3-b]indole was prepared from 5,6,7,8-tetrahydro-9H- pyrido[2,3-b1indole, sodium hydride and [if-morpholinoethyl chloride in dimethyl formamide in the manner as descrbied in Example I. The hydrochloride melted at 234-237 C.

Analysis for C17H25C12N3O calculated; C, 57.00%; H, 7.03%; Cl, 19.77%; N, 11.73%. Found: C1, 19.65%; N, 11.79%.

EXAMPLE 7 A solution of 5,6,7,8,9,10 hexahydro 11H cyclooct [4,5]pyrrolo[2,3-b]pyridine (5.0 g., 0.025 mole) in dimethyl formamide (50 ml.) was added to a suspension of sodium hydride (1.42 g., 0.0325 mole, of a 55% dispersion in mineral oil) in dimethyl formamide. The mixture was stirred for 1% hours after completed addition. A solution of fl-bromophenetole (5.03 g., 0.025 mole) in dimethyl formamide (50 ml.) was added over a period of 3 hours. The reaction mixture was stirred at room temperature for 17 hours, then at 50 C. for an additional period of 2 hours. The mixture was cooled and poured into 500 ml. water. A yellow solid formed; this was filtered ofi, washed, dried and recrystallized from aqueous ethanol to give 5,6,7,8,9,10-hexahydro-11-(2- phenoxyethyl) 11H cyc1ooct[4,5 ]pyrrolo[2,3 b]pyridine, 7.12 g. (88.9% yield) melting at 83-86 C. The hydrochloride was prepared by treating an alcoholic solution of the base with saturated alcoholic hydrogen chloride and diluting with ether. After recrystallizing from ethanol-ether, the salt melted at 213.5-217 C.

Analysis for C H ClN O calculated: C, 70.70%; H, 7.07% CI, 9.93%; N, 7.85%. Found: C, 70.83%; H, 7.01%; Cl, 9.9%; N, 7.73%.

In the same manner as disclosed in Example 1 or 7 using the appropriate starting materials, one may prepare the following compounds:

9 Z-pyrrolidinoethyl] -5 ,6,7, 8 -tetrahydro-9H-pyrido [2,3-b]indole 9 [Z-piperidinoethyl] -5,6,7, 8-tetrahydro-9H-pyrido [2,3 -b indole 9 2-piperazinoethyl] -5,6,7,8-tetrahydro-9H-pyrido [2, 3-b indole l1[2-(dimethylamino)Z-methylethyl]-5,6,7,8,9,10-

hexahydro-1 lH-cyclooct [4,5 pyrrolo 2,3-b] pyridine 13[3-(dimethylamino)propyl]-5,6,7,8,9,10,11,12-

octahydro- 1 3I-I-cyclodec- [4,5 pyrrolo 2,3-b pyridine.

Other compounds falling within the scope of the inventive concept may also be prepared as indicated:

11[3-aminopropyl]-5,6,7,8,9,10 hexahydro 11H-cyclooct-[4,5]pyrrolo[2,3-b]pyridine may be obtained by LiA1H4 reduction of the corresponding nitrile, which in turn is obtainable by treatment of the ll-unsubstituted compound with acrylonitrile.

11-[3 (methylamino)propyl]-5,6,7,8,9,10-hexahydro- 11H cyclooct[4,5]pyrrolo[2,3 b]pyridine may be obtained by treating the 3-aminopropyl product of the preceding example with chloral followed by a reduction step using lithium aluminum hydride. To obtain a dimethylaminopropyl chain, the product of the preceding example is treated with formic acid-formaldehyde under the usual conditions for a Leuchart reaction.

9-[2 (dimethylarnino)-2-(methyl)ethyl]-5,6,7,8-tetrahydro-9H-pyrido[2,3-b] indole may be obtained in the manner exemplified by Example 1 by using Z-dimethylaminoisopropylchloride as the aminohalide.

the nontoxic, acid-addition and quaternary ammonium salts thereof, wherein R represents a member of the group consisting of phenoxy-(lower)alky1, amino(lower)alkyl, (lower)alkylamino(lower)alkyl, di (lower)alky1amino (lower)alkyl, pyrrolidino(1ower)alkyl, piperidino(lower) alkyl, piperazino(lower)alkyl, and morpholino(1ower)alkyl, the term lower alkyl meaning alkyls having no more than 3 carbon atoms and n standing for the integer 6.

2. A compound of claim 1; wherein R is selected from the group consisting of phenoxy(lower)alkyl, di-(lower) alkylamino(lower)alkyl, and morpholino(lower)alkyl, and wherein the lower alkyl moiety has no more than 3 carbon atoms.

3. As a compound of claim 1; 11-[2-(diethylamino) ethyl] 5,6,7,8,9,10 hexahydro 11H cyclooct[4,5] pyrrolo [2,3 -b pyridine.

4. As a compound of claim 1; 11-[3-(dimethylamino) propyl] 5,6,7,8,9,10 hexahydro 11H cyclooct[4,5] pyrrolo[2,3-b]pyridine.

5. As a compound of claim 1; 5,6,7,8,9,l0-hexahydro- 11 (2-morpholinoethyl) 11H cyclooct[4,5]pyrrolo [2,3 -b pyridine.

References Cited UNITED STATES PATENTS 3,154,556 10/1964 Freed et al. 260-296 HENRY R. JILES, Primary Examiner A. L. ROTMAN, Assistant Examiner US. Cl. X.R. 

